A reduced model clarifies the role of feedback loops and time delays in the Drosophila circadian oscillator
A reduced model clarifies the role of feedback loops and time delays in the Drosophila circadian oscillator
复制标题
DOI：
10.1016/s0006-3495(02)75249-1
复制
发表时间：
2002-11-01
影响因子：
3.4
通讯作者：
Byrne, JH
中科院分区：
文献类型：
--
作者：
Smolen, P;Baxter, DA;Byrne, JH
虽然已经开发了几种对昼夜节律振荡至关重要的分子过程的详细模型，但它们的复杂性使得对振荡机制的直观理解变得困难。本研究的目的是减少以前开发的，详细的模型，以最小的代表性的转录调控在果蝇的昼夜节律必不可少的。简化模型只包含两个微分方程，每个都有时间延迟。包括负反馈环，其中PER蛋白通过结合dCLOCK转录因子来抑制PER转录。还包括一个正反馈回路，其中dCLOCK间接增强其自身的形成。该模型模拟昼夜节律振荡，光夹带，和相位响应曲线与实验定性相似。时间延迟被发现是必不可少的模拟与此模型的昼夜节律振荡。为了检验简化模型对分子数量波动的鲁棒性，构建了随机变量。强大的昼夜节律振荡和夹带光脉冲进行了模拟，平均每种基因产物的分子少于80个。当正反馈环被移除时，昼夜节律振荡仍然存在。此外，消除正反馈并没有减少随机波动或参数值的变化的振荡的鲁棒性。这种简化的模型可以帮助理解果蝇和其他生物体中的振荡机制，其中转录的反馈调节可能发挥重要作用。
Although several detailed models of molecular processes essential for circadian oscillations have been developed, their complexity makes intuitive understanding of the oscillation mechanism difficult. The goal of the present study was to reduce a previously developed, detailed model to a minimal representation of the transcriptional regulation essential for circadian rhythmicity in Drosophila. The reduced model contains only two differential equations, each with time delays. A negative feedback loop is included, in which PER protein represses per transcription by binding the dCLOCK transcription factor. A positive feedback loop is also included, in which dCLOCK indirectly enhances its own formation. The model simulated circadian oscillations, light entrainment, and a phase-response curve with qualitative similarities to experiment. Time delays were found to be essential for simulation of circadian oscillations with this model. To examine the robustness of the simplified model to fluctuations in molecule numbers, a stochastic variant was constructed. Robust circadian oscillations and entrainment to light pulses were simulated with fewer than 80 molecules of each gene product present on average. Circadian oscillations persisted when the positive feedback loop was removed. Moreover, elimination of positive feedback did not decrease the robustness of oscillations to stochastic fluctuations or to variations in parameter values. Such reduced models can aid understanding of the oscillation mechanisms in Drosophila and in other organisms in which feedback regulation of transcription may play an important role.